tbuckley/cabot-search huggingface dataset:
Abstract 5831: CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor associated macrophages
Authors: Cho-Hao Lin, Fatemeh Talebian, Yang Li, Jianmin Zhu, Bolin Zhao, Jin-Qing Liu, Sujit Basu, Xueling Pan, Xi Chen, Pearlly Yan, William E. Carson, Gang Xin, Haitao Wen, Ruoning Wang, Zihai Li, Qin Ma, Xue-Feng Bai
Journal: Cancer Research (2023)

Abstract CD200 is overexpressed in human solid tumors such as neuroblastoma and melanoma and is considered as an immune checkpoint molecule for dampening cancer immunity. However, how CD200 affects tumor microenvironment (TME) and host immunity is incompletely understood. In the present study, we evaluated the role of the CD200-CD200R pathway in TME using loss-of-function CD200R-/- mice, along with two clinically relevant, CD200-positive murine tumor models: the mouse neuroblastoma NB9464D and melanoma Yummer1.7. We found that comparing with the wild type mice, CD200R-/- mice were significantly more potent in rejecting these CD200+ tumors. Transcriptome analysis by single cell RNA sequencing demonstrated that tumors from CD200R-/- mice had more infiltration of CD45+ immune cells, including CD4+ and CD8+ T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effectors including CD8+ T cells and NK cells in combination, are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling differentially regulates the expression of chemokines in tumor-associated macrophages (TAMs). In the absence of CD200R, TAMs up-regulate CCL24 and CCL8 and down-regulate CXCL3, CXCL2, and CCL3 via activation of ERK and/or p38 MAP kinases. Increased expression of CCL24 in CD200R-deficient tumors resulted in increased infiltration of eosinophils, which also contributes to anti-tumor activity. Overall, we conclude that CD200R-mediated signaling, via interaction with CD200 on tumor cells, contributes to unfavorable TME primarily through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has significant implications in developing CD200-targeted immunotherapy of solid tumors. Citation Format: Cho-Hao Lin, Fatemeh Talebian, Yang Li, Jianmin Zhu, Bolin Zhao, Jin-Qing Liu, Sujit Basu, Xueling Pan, Xi Chen, Pearlly Yan, William E. Carson, Gang Xin, Haitao Wen, Ruoning Wang, Zihai Li, Qin Ma, Xue-Feng Bai. CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5831.
Abstract 5372: Supervised manifold learning and classification; application to expression data visualization and cancer prediction
Authors: James Webber, Kevin Elias
Journal: Cancer Research (2023)

Abstract Background: Manifold Learning (ML) has become essential in recent years for expression data visualization and dimension reduction. ML operates under the assumption that the data points lie on a manifold embedded in Euclidean space. The goal of ML is to learn an inverse embedding function to decipher the manifold structure. Cancer classification is a widely investigated application of expression profile data (e.g., miRNA) currently in the literature. The non-linear ML techniques commonly applied to expression data, such as t-distributed Stochastic Neighborhood Embedding (TSNE), Isomap, and Locally Linear Embedding (LLE), are intended for visualization, and cannot easily be applied to classification or unseen data, more generally. Such methods are also unsupervised, and do not factor in class information. Conventional linear ML methods, such as Principal Component Analysis (PCA), while applicable to unseen data and easy to use, are limited and can learn only linear manifolds. Results: We introduce a novel, non-linear ML technique, which incorporates class memberships, and is readily applicable to unseen data and classification. Specifically, we construct a series of neighborhood graphs which describe the manifold structure locally within each cluster and among the cluster centroids. Our objective function uses the neighborhood graph information to preserve the class separations and manifold structure in reduced dimension space, and we train a neural network to learn an explicit, inverse embedding function. This allows for fast visualization and classification of unseen data. The technique is compared against similar methods from the literature which use neural networks for ML, and is shown to offer improved cancer classification performance on expression data from The Cancer Genome Atlas (TCGA) and The Cancer Proteome Atlas (TCPA). Conclusion: We present a new, supervised ML technique designed specifically for classification, which can be efficiently applied to unseen data. The results show promise on multiple, large-scale expression data sets, and thus warrant further research into supervised ML methods for cancer classification and expression data visualization. Citation Format: James Webber, Kevin Elias. Supervised manifold learning and classification; application to expression data visualization and cancer prediction. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5372.
Abstract 6464: Antidepressant use and lung cancer risk and mortality: A meta-analysis of observational studies
Authors: Eunkyung Lee, David Li, Yongho Park, Alice Rodriguez-Fuguet, Xiaochuan Wang, Wen Cai Zhang
Journal: Cancer Research (2023)

Abstract Objectives: Recent preclinical studies suggested potential anticancer effects of antidepressant (AD) use in multiple cancers, but the effect on lung cancer in human studies remains unclear. This meta-analysis examined the effect of AD use on lung cancer incidence and mortality. Methods: Web of Science, Medline, CINAHL, and PsycINFO databases were searched to identify eligible studies published by June 2022. We conducted a meta-analysis using a random effects model to estimate pooled risk ratio (RR) and 95% confidence interval (CI) for comparing those with AD use and non-use. Heterogeneity was examined using Cochran’s Q test and inconsistency I2 statistics. The methodological quality of selected studies was assessed using the Newcastle-Ottawa Scale for observational studies. Results: The meta-analysis, including 11 publications involving 1913172 participants, showed that AD use significantly increased lung cancer risk by 11% (RR= 1.11; 95% CI= 1.01, 1.22; I2= 74.3%; n= 6); however, all-cause mortality was not affected by AD use (RR= 1.05; 95% CI= 0.68, 1.58; I2= 90.1%; n= 4) while lung cancer-specific mortality could be reduced by 32% from onse study. Subgroup analysis showed that serotonin and norepinephrine reuptake inhibitors (SNRIs) were associated with an increased lung cancer risk (RR= 1.38; 95% CI= 1.07, 1.78), but selective serotonin reuptake inhibitors (RR= 1.05; 95% CI=0.91, 1.21) and tricyclic antidepressants (RR= 1.09; 95% CI=0.95, 1.26) were not. In addition, variations in the definition of AD use could be the source of heterogeneity of observed effects. The quality of selected studies was good (n= 5) to fair (n= 6). Conclusions: Evidence suggests that AD use was associated with an elevated risk of lung cancer but not with all-cause mortality. More research is needed to precisely estimate the effect of AD use on lung cancer-specific mortality. (Funding: University of Central Florida Center for Behavioral Health Research and Training; Registration: PROSPERO; registration number: CRD42022350719) Citation Format: Eunkyung Lee, David Li, Yongho Park, Alice Rodriguez-Fuguet, Xiaochuan Wang, Wen Cai Zhang. Antidepressant use and lung cancer risk and mortality: A meta-analysis of observational studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6464.
Abstract 1090: Dominant-negative <i>TP53</i> variants confer radiation resistance in endometrial cancer
Authors: Aaron Petty, Arda Durmaz, Brian Yard, Jacob Scott, Roberto Vargas
Journal: Cancer Research (2023)

Abstract Introduction: High-grade endometrial cancers (EC) belonging to the “serous-like” cluster are known to portend a worse clinical outcome. The direct contribution of commonly identified TP53 variants on radiotherapy (RT) response has not been demonstrated in EC. Methods: To assess the impact of TP53 variants, allelic frequency, and p53/p21 signaling on radio-resistance in vitro, we utilized a high-throughput radiation assay and intron targeting CRISPR-Cas9 knockout approach in two low copy-number/TP53 wild-type EC cell lines (JHUEM1/JHUEM2). This approach facilitated TP53 cDNA complementation in a TP53-null background without significant impact from copy-number burden. The effect on radiation response was determined using high-throughput methodology and area under the curve (AUC) calculation along 5 dose-points. All experiments were carried out using 2 monoclonal isolates for each guide RNA (4 total replicates) and 2 non-targeting controls. Results: Knockout (KO) of wild-type TP53 resulted in loss of downstream p21 signaling and increased radio-resistance, demonstrating the role of p53 signaling on RT response. Complementation with five common TP53 missense variants (Y220C, R273C, R273H, R248Q, R248W) into the KO cell lines led to increased p53 accumulation without an effect on p21 signaling or RT response. Complementation into the WT cell lines, mimicking tumors with low allelic frequency/heterozygous mutations, led to abrogation of p21 signaling and increased radio-resistance, establishing their gain-of-function/dominant-negative impact. Conclusions: Our findings directly implicate TP53 status on radiotherapy response in EC, providing biologic rationale for the clinical observation that these patients may benefit from chemotherapy. Additionally, our findings demonstrate that dominant-negative variant alleles similarly impact RT response by abrogating p21 signaling. Citation Format: Aaron Petty, Arda Durmaz, Brian Yard, Jacob Scott, Roberto Vargas. Dominant-negative TP53 variants confer radiation resistance in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1090.
Abstract 1061: Digital phenotyping in pediatric oncology: the development of a mobile application for outpatients follow up
Authors: Abeer Abd Elmoneim, Marwan Aly
Journal: Cancer Research (2023)

Abstract Introduction and aim: Outpatients follow up usually depends on recall of data. This recall is subjective to patients' or gaurdians' memory. Smart phones can capture a lot of data either through inbuilt sensors and connected devices or through the engagement of users. These mobile digital devices brought forth innovative methods of acquiring personal healthcare data. In pediatric oncology, the need for accurate record of serious symptoms while patients are at home is a challenge in outpatients' care. In a step towards collecting real-time events that happened during the outpatient follow up, we develop a smart phone application that can record data actively by patients or their guardians in situ and on time of its occurrence, which can improve the follow up process and facilitate a decision making by the physician that based on objective data more than subjective ones. We aim in this research to generate an easy-to-use mobile application for home follow up of pediatric oncology patients. Methods: Predictive characteristics of digital features either extracted from studies or generated by field experts were reported to map the associations between digital feature and the disease. Identified digital features were aggregated into categories that represent interpretable serious signs. A smart phone application with the identified digital features is developed with the help of Valid Solutions, LLC (Health Technology Limited Liability Company, USA). Expected Results: Early and accurate detection of serious symptoms through in situ and on real-time can help to better delivery of required health care. Conclusion: This research will provide a high level vision on relationships between digital phenotyping and pediatric oncology illnesses and will help to identify gaps requiring further research. It will highlight the digital features with higher value of prediction of serious signs. Citation Format: Abeer Abd Elmoneim, Marwan Aly. Digital phenotyping in pediatric oncology: the development of a mobile application for outpatients follow up [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1061.
Abstract 2213: Longitudinal tracking of circulating rare events in the liquid biopsy of stage III-IV NSCLC patients during treatment
Authors: Lily Bai, George Courcoubetis, Jorge Nieva, Jeremy Mason, Peter Kuhn, Stephanie Shishido
Journal: Cancer Research (2023)

Abstract Lung cancer is the most common cause of cancer-related death in the United States. Non Small Cell Lung Cancer (NSCLC) is the most prevalent subtype of lung cancer diagnoses, with significantly worse survival rates as clinical staging progresses. The purpose of this study was to determine the prognostic utility of longitudinal peripheral liquid biopsy as a treatment monitoring tool in stage III-IV NSCLC patients throughout treatment. Liquid biopsy represents a way for physicians to non-invasively continuously monitor and understand tumor progression through analyzing serial patient blood samples. This allows for real-time, in depth analysis of patient status throughout the treatment process. This study used the third generation, enrichment-free High-Definition Single Cell Assay (HDSCA3.0) workflow to detect and characterize rare events in the 48 peripheral blood samples collected from a cohort of 10 stage III-IV NSCLC patients undergoing various treatments. This workflow uses 4 fluorescent channels corresponding to 5 biomarkers. While circulating tumor cells (CTCs) have been shown to be effective as a prognostic tool for measuring treatment efficacy and patient response to treatment, we have additionally identified 6 additional rare cell phenotypes with variable cytokeratin expression, and 3 types of oncosomes. We have established a liquid biopsy profile that is unique to NSCLC as compared to 50 normal donors. Within this cohort, we found significantly higher amounts of rare cells and oncosomes in patient cohorts as compared to normal donors, highlighting the potential utility of both cellular and oncosome subtypes in disease monitoring. In addition, these rare events differ drastically in morphological parameters and channel expression, and also display temporal heterogeneity. Through the analysis of peripheral blood samples across time and treatment methodologies, we observed significant association between liquid biopsy analytes and progression-free and overall survival, supporting the utility of liquid biopsy as a clinical tool. Understanding the dynamics behind these rare groups throughout the courses of treatment may help improve prognostic utility of liquid biopsy. Citation Format: Lily Bai, George Courcoubetis, Jorge Nieva, Jeremy Mason, Peter Kuhn, Stephanie Shishido. Longitudinal tracking of circulating rare events in the liquid biopsy of stage III-IV NSCLC patients during treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2213.
Abstract 3808: MicroRNA-206 drives antitumor immunity by disrupting the communication between Kupffer cells and Tregs
Authors: Guisheng Song, Ningning Liu
Journal: Cancer Research (2023)

Abstract Kupffer cells (KCs) account for 15% of the total liver cells. However, their roles in hepatocellular carcinoma (HCC) is poorly described. Clec4fCre-tdTomato knock-in mice expressing Cre recombinase and tdTomato-NLS under the KC-specific Clec4f promoter were hydrodynamically injected with oncogenic AKT and Nras (AKT/Ras) to induce HCC. A LoxP-stop-LoxP (LSL) system was used to express miR-206 in KCs of mice. AKT activation was observed in hepatocytes and KCs of HCC patients. Hydrodynamic injection (HDI) of AKT/Ras led to activation of AKT signaling in KCs and hepatocytes. AKT/Ras mice developed lethal HCC within 6-8 weeks post injection. Activation of AKT signaling led to M2 polarization of KCs, increased hepatic Tregs and exhaustion of CTLs. MicroRNA (miR) profiling revealed that AKT/Ras impaired miR-206 biogenesis in KCs by driving translation of Yin Yang 1 (YY1), a transcription repressor of miR-206. HDI of miR-206 into AKT/Ras mice fully prevented HCC, while all control mice died of HCC 6-8 weeks post injection. However, HDI of miR-206 only transfected ~ 20% of hepatocytes, indicating that it is unreasonable to conclude that the full prevention of HCC in AKT/Ras/miR-206 mice is caused by inhibited proliferation of HCC cells. We, therefore, posited that miR-206-mediated recovery of immune surveillance, at least in part, accounted for the full prevention of HCC in AKT/Ras/miR-206 mice. We next used the LSL system to overexpress miR-206 in KCs of Clec4fCretdTomato mice injected with AKT/Ras. KC-specific expression of miR-206 fully prevented HCC in AKT/Ras mice, while 100% control mice died of HCC. Mechanistically, AKT signaling in KCs drove CCL22 (C-C motif chemokine ligand 22) production by phosphorylating β-catenin that activates transcription of Ccl22. In contrast, miR-206 disrupted β-catenin signaling by targeting LEF1 (lymphoid enhancer-binding factor 1), an “architectural” transcription factor of β-catenin. CCL22 recruits Tregs. Indeed, KC-specific expression of miR-206 led to elevated CCL22, M2 to M1 transition of KCs, reduced hepatic Tregs, and elevated CTLs. Depletion of CTLs in AKT/Ras mice fully offset the ability of miR-206 to prevent HCC. Conclusions: AKT-educated KCs initiate Treg recruitment via a regulatory loop consisting of YY1, β-catenin/LEF1, miR-206, and CCL22; once this loop is activated, AKT activates β-catenin axis, which drives CCL22 production, Treg recruitment and HCC growth; while KC-specific expression of miR-206 reversed this process by blocking β-catenin axis in KCs. miR-206 represents a novel immunotherapy against HCC. Citation Format: Guisheng Song, Ningning Liu. MicroRNA-206 drives antitumor immunity by disrupting the communication between Kupffer cells and Tregs. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3808.
Abstract 5018: PROTAC degraders of CDK8/CDK19 Mediator kinases potently suppress multiple myeloma proliferation
Authors: Li Zhang, Jing Li, Charles E. Dowling, Eugenia V. Broude, Igor B. Roninson, Campbell McInnes, Mengqian Chen
Journal: Cancer Research (2023)

Abstract CDK8 and CDK19 are kinase components of the CDK module that comprises CDK8 or CDK19 together with their binding partner cyclin C (CCNC) and two other proteins; the CDK module is associated with transcriptional Mediator complex. CDK8/19 Mediator kinases potentiate transcription induced by different signals, regulate protein levels of Mediator complex components and protect CCNC from proteolytic degradation; the latter activity is exerted in a kinase-independent manner. CDK8/19 kinase inhibitors have entered clinical trials for solid tumors and leukemias. To extend the effects of CDK8/19 inhibition and to suppress their kinase-independent activities, we have developed three series of PROteolysis TArgeting Chimeras (PROTACs) based on different selective inhibitors of CDK8/19 kinases, connected via different linkers to a moiety binding cereblon (CRBN) E3 ligase. The most potent PROTACs degraded both CDK8 and CDK19 in different cell types with DC50s of 10-20 nM. RNA-Seq analysis of 293 cells treated with a CDK8/19 kinase inhibitor or PROTAC showed that the bulk of the PROTAC’s transcriptomic effects matched the effects of the kinase inhibitor. In contrast to the kinase inhibitors, CDK8/19-degrading PROTACs also induced CCNC degradation. Cancer Dependency Map (DepMap) analysis revealed that multiple myelomas (MM), where CRBN is an established therapeutic target, show greater dependency on CCNC than most of the tumor cell lines. We have tested two strongly CCNC-dependent MM cell lines and one CCNC-independent MM line for sensitivity to different CDK8/19 kinase inhibitors and PROTACs. Kinase inhibitors showed low to moderate anti-proliferative activity in all three MM lines, whereas CDK8/19 PROTACs were an order of magnitude more potent than the kinase inhibitors in the two CCNC-dependent MM lines (IC50s of 20-30 nM) but not in the CCNC-independent line. The effects of CDK8/19-degrading PROTACs were stronger than those of the CRBN-targeting drug pomalidomide (approved for MM), a CRBN-binding PROTAC acting on androgen receptor or a CDK8 degradation-inactive PROTAC analog containing CDK8/19- and CRBN-binding moieties. These results suggest the potential of CDK8/CDK19-degrading PROTACs for the treatment of MM. Citation Format: Li Zhang, Jing Li, Charles E. Dowling, Eugenia V. Broude, Igor B. Roninson, Campbell McInnes, Mengqian Chen. PROTAC degraders of CDK8/CDK19 Mediator kinases potently suppress multiple myeloma proliferation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5018.